Multiple myeloma (MM) affected 14,400 new individuals in the United States in 2001, with 50,000 total patients, and remains incurable despite conventional and high dose therapies. Novel therapeutic interventions are therefore urgently needed with targets unique to the tumor cell and its microenvironment. The major goal of the current proposal, "Host-Tumor Cell Interactions in Myeloma: Therapeutic Applications", is to develop novel therapies targeting host-tumor cell interactions to overcome drug resistance and achieve long-term disease free survival and potential cure of MM. This Program builds upon and extends progress during the prior funding period and now has three major goals. First, we will attempt to therapeutically exploit the interaction of the allogeneic donor immune response against MM and define target antigens for novel therapeutics (Project by Ritz). Second, we will attempt to augment autologous anti-MM immunity using vaccination strategies, and similarly identify novel target antigens (Project by Munshi). In each case molecular identification and validation of novel targets will derive MM specific immune therapies. Importantly, our preclinical in vitro as well as in vivo animal models of MM cells in the BM milieu, demonstrate that novel agents targeting the MM cell-host bone marrow (BM) interaction can overcome classical drug resistance. Our derived clinical trials show that these agents can achieve responses, in some cases complete responses, in the majority of patients with MM refractory to all known current therapies. Therefore a new and important goal of this Program (Project by Anderson) is to define and validate MM-host interactions as targets in a new treatment paradigm for MM. Administrative and Research Nursing (A) and Biostatistics/ Bioinfomatics (B) Cores will assist in design, conduct, analysis, and reporting of laboratory and clinical studies. Immune Assessment Core (C) will provide immunological monitoring after these novel therapies. This Program therefore represents an integrated, interrelated, and interdependent series of three Projects and three Cores which interact on both a scientific and clinical level. It is anticipated, both within and between projects, that laboratory based mechanistic studies will translate to clinical studies, and that conversely, observations from clinical protocols will suggest new basic investigations. Ultimately our goal is to validate MM-host cell interactions as a target for novel therapeutics to improve patient outcome in MM.